Levels of lipoprotein(a) in normal and compromised pregnancy

OBJECTIVE: To study maternal lipoprotein(a) levels in normal pregnancy and in pregnancy with evidence of vascular disease in the maternal uteroplacental circulation defined by Doppler ultrasound study. SAMPLES: Maternal venous blood was collected from 75 normal pregnant women and 68 pregnant women with evidence of potential uteroplacental vascular disease identified by Doppler ultrasound study. METHODS: Plasma lipoprotein(a) levels in maternal blood were measured using an enzyme-liked immunosorbent assay method. MAIN OUTCOME MEASURES: Plasma lipoprotein(a) levels and pregnancy outcome were examined. RESULTS: None of the normal group had lipoprotein(a) levels greater than 30 mg/dl, a cutoff level which has been associated with increased risk of atherosclerosis. 28 of the 68 women with uteroplacental insufficiency had lipoprotein(a) levels greater than this cutoff level. In this group there was a statistically significant higher prevalence of preeclampsia in comparison with women with a normal lipoprotein(a) level (p < 0.001). The lipoprotein(a) level was significantly higher in severe (n = 13, median 60.5 mg/dl, P < 0.001] than in mild preeclampsia (n = 5, median 34 mg/dl). Those with high levels (> 30 mg/dl) exhibited significantly more adverse indices of fetal outcome. CONCLUSION: This study has demonstrated that high levels of lipoprotein(a) interfere with uteroplacental circulation and play a role in the pathophysiology of preeclampsia. Lipoprotein(a) concentrations are associated with the severity of the disease. We suggest that high levels of lipoprotein(a) might affect the placenta and fetus.     

Co-expression of parathyroid hormone and chromogranin A in secondary hyperparathyroidism: a functional marker for secretory activity of hyperplastic nodules

The relationship between secretion of parathyroid hormone (PTH) and biologic characteristics, including cell proliferation or monoclonality, is not yet fully understood. To evaluate secretory activity of glands or nodules histopathologically, we focused on the co-expression of chromogranin A (CgA) and parathyroid hormone (PTH) in each gland or nodule. A total of 55 glands from 38 patients with normal parathyroid glands, hyperplastic glands (diffuse and nodular) and primary adenomas were compared. Co-expression of PTH and CgA was decreased to 44.4% in diffuse hyperplastic glands, and to 39.6% in 91 hyperplastic nodules, in contrast to normal glands and primary adenomas that showed constant co-expression of PTH and CgA. Immunohistochemical study of PTH showed a coarse granular pattern predominantly in PTH-positive/CgA-positive nodules, and a dot-like pattern mainly in PTH-positive/CgA-negative nodules. Laser scanning microscopy and immunoelectron microscopy confirmed that a dot-like pattern is based on a positive reaction of PTH at the Golgi apparatus. MIB-1 LI was 12.6 +/- 11.6 in PTH-positive/CgA-positive, and 19.3 +/- 27.3 in PTH-positive/CgA-negative nodules. In conclusion, a combination of PTH and CgA could provide more information about the physiologic state of secretory activity of each nodule than does the simple observation of PTH immunoreactivity.     

Autopsy case of multiple anomalies with hypoplastic cerebrum,eyes, and endocrine organs,mimicking Micro syndrome

We report an autopsy case of multiple anomalies with severe micrencephaly, bilateral microphthalmos, and hypoplastic endocrine organs. We examined expressions of calcium-binding proteins and hypothalamic and pituitary hormones. A female proband presented with microcephaly, microphthalmia, and psychomotor development delay. At the age of 23 years, she died of cardiorespiratory failure. The endocrine organs demonstrated severe underdevelopment, and the hypoplastic eyeballs had remnant lens, vitreous hemorrhage, and retinal detachment. The brain weighed 260 g; the cerebrum, cerebellum, and brain stem were extremely small; and the tertiary sulci were absent in the cerebral surface. The cross-sectional area of cerebral cortex was reduced to about one third of those in the control, although six-layered lamination, density of pyramidal neurons, and expressions of calcium-binding proteins were comparatively preserved in the cerebral cortex. The third ventricle was hypoplastic, and the bilateral thalami appeared to be fused and the hippocampus was unrolled, whereas the corpus callosum was preserved. In the hypothalamus, the paraventricular nucleus was only identified, and the adenohypophysial somatotrophs were reduced. This may be the first autopsy report of Micro syndrome, which is characterized by microcephaly, brain malformations, optic atrophy, and hypogenitalism, although the case lacked agenesis of the corpus callosum.     

A naturally occurring p73 mutation in a p73-p53 double-mutant lung cancer cell line encodes p73 alpha protein with a dominant-negative function

p73, a close homolog of p53 tumor suppressor, induces growth arrest and apoptosis. However, its role in cancers is controversial because of the rarity of p73 mutations, lack of tumors in p73-knockout mice, and the presence of multiple isotypes, among which ΔN isotypes inhibit the function of TA isotypes. We analyzed three naturally occurring p73 mutants found in lung cancer cell lines, NCI-H1155, DMS 92 and A427. NCI-H1155 is a cell line that has a p73 mutation [p73(G264W)] in the DNA-binding domain, as well as a p53 mutation [p53(R273H)], which is frequently found in human cancers and has a "gain-of-function" characteristic. p73α(G264W) not only lacks transactivation activity itself, but also suppressed the transactivation activity of the wild-type p73α in a dose-dependent manner, indicating that p73α(G264W) is a dominant-negative mutant. p73α(G264W) failed to suppress colony formation. We tested two other mutations, p73(Del418) in DMS 92 and p73(Del603) in A427. Both mutants retained similar levels of transactivation activity and suppression of colony formation to those of wild-type p73. The biological significance of these two mutations is unclear. In NCI-H1155 cells the coexistence of mutations that abrogate the normal functions of p73 and p53 may indicate that each mutation confers an additive growth advantage upon the cells.     

Docetaxel and carboplatin combination chemotherapy for recurrent endometrial cancer

 There is no consensus regarding the optimal chemotherapy for endometrial cancer patients, and a need for better chemotherapy is evident. Two individuals with recurrent metastatic endometrial cancer treated with docetaxel and carboplatin combination chemotherapy are presented here. Both cases showed objective response to the chemotherapy (one complete response and the other partial response); response duration was 7 and 18 months, respectively. One patient who achieved complete response is alive without disease for 12 months after recurrence. Adverse effects in this regimen were mild and tolerable. Docetaxel in combination with carboplatin may be active agents for patients with metastatic endometrial cancer. Received: August 27, 2002 / Accepted: November 28, 2002 Correspondence to:Y. Aoki     

Characterization of beta-adrenergic receptor sequestration by newly developed whole cell binding assays

Upon agonist binding, beta-adrenergic receptors sequestrate from the cell surface plasma membrane to cytosol. In the present study, we examine the kinetics of sequestration of beta1-adrenergic receptor and beta3-adrenergic receptor subtypes by radioligand binding assays using whole cells ('whole cell binding assays'). We found that HEK293T cells, but not COS1 cells, were readily and uniformly detached from the culture dish upon exposure to ice-cold phosphate-buffered saline. Using this property of HEK293T cells, we conducted whole cell binding assays using a hydrophilic antagonist ([3H]CGP-12177) and HEK293T cells transiently overexpressing human beta1-adrenergic receptor or beta3-adrenergic receptor. The Bmax and Kd values were 5.96 +/- 0.97 pmol/mg protein and 1 +/- 0.23 nM for the beta1-adrenergic receptor, and were 1.84 +/- 0.13 pmol/mg protein and 44.7 +/- 2.5 nM for the beta3-adrenergic receptor, respectively. Isoproterenol treatment, but not 6-[3-(dimethylamino)propionyl]forskolin treatment, for 2 h resulted in a dose-dependent loss of the number of the cell surface beta1-adrenergic receptor. At 100 microM, 36.6 +/- 5.7% of the cell surface beta1-adrenergic receptor was lost. In contrast, the cell surface beta3-adrenergic receptor number remained unchanged with isoproterenol treatment. Thus, beta1-adrenergic receptor sequestrates upon agonist stimulation but the same agonist stimulation does not induce beta3-adrenergic receptor sequestration, as demonstrated by our whole cell binding assays.     

Enhanced Incorporation of 1-β-D-Arabinofuranosylcytosine by Pretreatment with Etoposide

We examined the effects of timing of administration of etoposide on cytosine arab-inoside (ara-C) incorporation into DNA in L1210 ascites tumor. At 1 hr after injection of ara-C, 3-hr and 6-hr pretreatments with 15 mg/kg of etoposide increased ara-C incorporation to more than 200% as compared to that of ara-C given alone. Simultaneous administration of etoposide, however, decreased ara-C incorporation to 33% of that of ara-C alone. These results might explain the previously reported sequence dependency of the antitumor effect of etoposide and ara-C.     

Accumulated allelic losses in the development of invasive urothelial cancer

To investigate the roles of allelic loss in the development of urothelial cancer, loss of heterozygosity was examined on 7 chromosomal arms in 49 cases of urothelial cancer of various grades and stages. Loss of heterozygosity was found on alleles in order of frequency as follows: 9q (21/38, 55%), 11p (20/44, 45%), 17p (18/42,43%), 13q (10/39,26%), 3p (8/41, 20%), 10q 2/29, 7%) and 1p (1/36, 3%). lnvasive (high-grade or ≥pT2) tumors showed the loss of 17p (13/16,81%) and the loss of 13q (7/16, 44%) with significantly higher frequencies than non-invasive (grade 1-2 ≤_pTI ) tumors. Although the loss of 3p and the loss of 11p were also more frequently associated with the invasive phenotypes, the loss of 11p was detected in a considerable number (9 of 26,35%) of non-invasive tumors. Our results indicate that the loss of 11p might generally occur at an earlier stage before the loss of 3p, 13q or 17p in tumor progression. Since no correlation was found between the loss of 9q and the tumor grade or stage, this genetic alteration appears to be unrelated to invasiveness, and could be one of the initial events in tumorigenesis. Although accumulated allelic losses of 3p, 11p, 13q and 17p are considered to be involved in the development of the invasive type of urothelial cancers, these multiple genetic alterations may have already occurred in some pathologically non-invasive urothelial cancers. Furthermore, there appears to be some variation in the pattern of cumulative allelic loss.